Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions.
Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions.
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作者：
Suzuki K;Nishi K;Takabuchi S;Kai S;Matsuyama T;Kurosawa S;Adachi T;Maruyama T;Fukuda K;Hirota K
前列腺素E1（PGE 1），在药学上称为阿替地尔，具有血管舒张特性，广泛用于各种临床环境。除了急性血管舒张特性外，PGE 1还可以通过改变血管细胞的蛋白质表达来发挥有益作用。据报道，PGE 1是通过上调VEGF表达的有效的血管生成刺激剂，其在转录因子缺氧诱导因子1（HIF-1）的控制下。然而，这种现象背后的分子机制在很大程度上是未知的。在本研究中，我们研究了PGE 1诱导人主动脉平滑肌细胞（HASMCs）和人脐静脉内皮细胞（HUVECs），这两种血管来源的细胞中HIF-1激活和VEGF基因表达的机制。在20%O2条件下用临床相关浓度的PGE 1处理HUVECs和HASMCs，并研究HIF-1蛋白表达。HIF- 1α蛋白和HIF-1下游基因的表达在20%O2条件下较低，在20%O2条件下，与暴露于1%O2条件下相当，在HUVECs和HASMCs中以剂量和时间依赖性的方式对PGE 1处理作出反应。使用EP受体特异性激动剂和拮抗剂的研究表明，EP 1和EP 3对PGE 1诱导的HIF-1活化至关重要。在体外血管通透性测定使用HUVECs表明，前列腺素E1增加血管通透性的HUVECs。因此，我们证明，PGE 1诱导HIF- 1α蛋白表达和HIF-1激活在非缺氧条件下，也提供证据表明，多个信号转导通路的活性下游的EP 1和EP 3受体是HIF-1激活所必需的。
Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation.
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巨噬细胞迁移抑制因子以p53依赖性方式激活缺氧诱导因子。
影响因子：
3.7
作者：
Oda, Seiko;Oda, Tomoyuki;Nishi, Kenichiro;Takabuchi, Satoshi;Wakamatsu, Takuhiko;Tanaka, Tomoharu;Adachi, Takehiko;Fukuda, Kazuhiko;Semenza, Gregg L.;Hirota, Kiichi
通讯作者：
Hirota, Kiichi
DOI：
10.1038/nri2607
发表时间：
2009-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.3
作者：
Cattaneo, MG;Pola, S;Vicentini, LM
通讯作者：
Vicentini, LM
影响因子：
4.8
作者：
Hirota, K;Fukuda, R;Semenza, GL
通讯作者：
Semenza, GL
影响因子：
3.6
作者：
Ji, Ruyue;Chou, Chih-Ling;Regan, John W.
通讯作者：
Regan, John W.